Genetic factors contribute to cardiac arrhythmias. All arrhythmia genes identified to date encode important cardiac ion channel subunits, indicating that ion channel dysfunction underlies arrhythmia susceptibility. Our preliminary data show that several novel arrhythmia genes await discovery, including genes responsible for syndactyly-associated long QT syndrome, Andersen's syndrome, familial sick sinus syndrome and drug-induced long QT syndrome. The goal of this proposal is to define and characterize these genes and encoded proteins with a long-term goal of improving prediction, prevention and treatment. The specific aims are: 1. Define and characterize genes responsible for syndactyly-associated long QT syndrome; 2. Deflne and characterize genes responsible for unlinked Andersen's syndrome; 3. Define and characterize genes responsible for familial sick sinus syndrome; 4. Define and characterize common variants in SCN5A that contribute to drug-induced long QT syndrome. Our preliminary data have defined sufficient patient material for these studies, but we will continue to ascertain and phenotypically characterize individuals and families with these disorders as this will increase the likelihood of success. We have defined specific candidate genes for each of these disorders, including Kir2.4, HCN pacemaker, L-type calcium, T-type calcium, SCN5A and other cardiac ion channel genes. We will test the candidacy of these genes using linkage and mutational analyses. We will identify additional candidate genes using the positional cloning-candidate gene and positional cloning approaches. Once defined, we will characterize each disease gene by Northern analysis of human tissues and by functional expression in Xenopus oocytes. Site-directed mutagenesis will be used to introduce disease-associated mutations in these genes. The physiologic consequences of these mutations will be defined by biophysical analysis of wild-type and mutant channels expressed in oocytes and mammalian cells.